Tobacco dependence is a disorder characterized by compulsive tobacco smoking and the appearance of a withdrawal syndrome upon the cessation of tobacco smoking. Nicotine is the major psychoactive ingredient of tobacco smoke that induces dependence. Tobacco smoking has been associated with cancers in nearly all organs and a large number of chronic diseases. It has been estimated that smoking leads to the death of 440,000 Americans each year and reduces the life span of smokers by and average of 14 years. Negative reinforcement processes (i.e., anhedonia) contribute to the maintenance of tobacco smoking. A majority of the tobacco smokers relapse within one week after their cessation attempt when affective withdrawal symptoms are most severe. This suggests that treatments that reverse the nicotine withdrawal syndrome may significantly increase the rates of successful smoking cessation attempts. Therefore, the overall aim of our studies is to investigate the neuronal substrates that may mediate the affective symptoms of nicotine withdrawal. The rat intracranial self-stimulation paradigm will be used to assess the affective signs of nicotine withdrawal. Nicotine withdrawal in rats is associated with elevations in brain reward thresholds (i.e., deficit in brain reward function) that are analogous to the anhedonia experienced by smokers upon a cessation attempt. The first specific aim is to examine the role of the "stress" peptide corticotropin-releasing factor (CRF) in parts of the extended amygdala in nicotine withdrawal. The extended amygdala is a large brain structure involved in emotion and motivation. It is expected that antagonism of CRF receptors in subcomponents of the extended amygdala reverse the affective signs of nicotine withdrawal in rats. The second specific aim is to examine the role of the "anti-stress" peptide neuropeptide Y (NPY) in subcomponents of the extended amygdala in nicotine withdrawal. It is expected that stimulation of NPY receptors in parts of the extended amygdala will alleviate the affective nicotine withdrawal signs. These proposed studies will provide information about the neuronal systems underlying nicotine withdrawal and may thereby contribute to the development of new and improved pharmacotherapies for smoking cessation. [unreadable] [unreadable]